All forms of diabetes are characterized by chronic hyperglycemia and the development of diabetes-specific microvascular pathology in the retina, renal glomerulus and peripheral nerve. As a consequence of its microvascular pathology, diabetes is a leading cause of blindness, end-stage renal disease and a variety of debilitating neuropathies. Diabetes is also associated with accelerated atherosclerotic macrovascular disease affecting arteries that supply the heart, brain and lower extremities. As a result, patients with diabetes have a much higher risk of myocardial infarction, stroke and limb amputation. Large prospective clinical studies show a strong relationship between glycaemia and diabetic microvascular complications in both type 1 and type 2 diabetes (The Diabetes Control and Complications Trial Research Group. N. Engl. J. Med. 329, 977–986 (1993); UK Prospective Diabetes Study (UKPDS) Group Lancet 352:837–853 [1998]).
Hyperglycaemia and insulin resistance both seem to have important roles in the pathogenesis of macrovascular complications (UK Prospective Diabetes Study (UKPDS) Group Lancet 352:837–853 [1998]). Diabetes-specific microvascular disease in the retina, glomerulus and vasa nervorum has similar pathophysiological features. Early in the course of diabetes, intracellular hyperglycaemia causes abnormalities in blood flow and increased vascular permeability. This reflects decreased activity of vasodilators such as nitric oxide, increased activity of vasoconstrictors such as angiotensin II and endothelin-1, and elaboration of permeability factors such as vascular endothelial growth factor (VEGF). Quantitative and qualitative abnormalities of extracellular matrix contribute to an irreversible increase in vascular permeability.
With time, microvascular cell loss occurs, in part as a result of programmed cell death. This results in progressive capillary occlusion due both to extracellular matrix overproduction induced by growth factors such as transforming growth factor-β (TGF-β), and to deposition of extravasated periodic acid Schiff-positive plasma proteins. Hyperglycaemia may- also decrease production of trophic factors for endothelial and neuronal cells. Together, these changes lead to oedema, ischaemia and hypoxia-induced neovascularization in the retina, proteinuria, mesangial matrix expansion and glomerulosclerosis in the kidney, and multifocal axonal degeneration in peripheral nerves.
The pathogenesis of arteriosclerosis in non-diabetics has been extensively described in recent reviews, and begins with endothelial dysfunction (Lusis, Nature 407:233–241 [2000]). In diabetic arteries, endothelial dysfunction seems to involve both insulin resistance specific to the phosphatidylinositol-3-OH kinase pathway and hyperglycaemia. Pathway-selective insulin resistance results in decreased endothelial production of the anti-atherogenic molecule nitric oxide, and increased potentiation of proliferation of vascular smooth muscle cells and production of plasminogen activator inhibitor-1 (PAI-1) via the Ras-Raf-MEK kinase mitogen-activated protein (MAP) kinase pathway (Hsueh and Law, Am. J. Med. 105:4S–14S [1998]). Hyperglycaemia itself also inhibits production of nitric oxide in arterial endothelial cells stimulates production of PAI-1 (Williams et al., Circulation 97:1695–1701 [1998]; Du et al., Proc. Natl Acad. Sci. USA 97:12222–12226 [2000]).
Both insulin resistance and hyperglycaemia have also been implicated in the pathogenesis of diabetic dyslipidaemia. The role of insulin resistance has been reviewed recently (Ginsberg, J. Clin. Invest 106: 453–458 [2000]). Hyperglycaemia seems to cause raised levels of atherogenic cholesterol-enriched apolipoprotein B-containing remnant particles by reducing expression of the heparan sulphate proteoglycan perlecan on hepatocytes. Associations of arteriosclerosis and arteriosclerosis risk factors with glycemia have been shown over a broad range of glucose tolerance, from normal to diabetic. Postprandial hyperglycemia may be more predictive of atherosclerosis than is fasting plasma glucose level or haemoglobin AIc (Temelkova-Kurktschiev et al., Diabetes Care 12:1830–1834 [2000]).
Thus, the art is in need of therapies that specifically target the underlying biochemical causes of diabetes complications.